Sirtuins Control Heart Failure Immunity Through Macrophage Reprogramming

Heart failure (HF) is a severe, end-stage cardiovascular syndrome with persistently high morbidity and mortality worldwide. Despite advances in standard care, therapeutic options remain limited, driving urgent interest in the molecular underpinnings of HF progression — particularly the role of immune regulation in cardiac remodeling.

This review focuses on the Sirtuin family of NAD+-dependent deacetylases (SIRT1–SIRT7) and their capacity to regulate macrophage polarization — the dynamic shift between pro-inflammatory (M1) and anti-inflammatory/reparative (M2) phenotypes. In heart failure, dysregulated macrophage polarization contributes to chronic inflammation, fibrosis, and impaired cardiac repair. Sirtuins emerge as central coordinators of this process across three interconnected domains.

First, sirtuins reshape macrophage metabolism by modulating glucose oxidation, lipid utilization, and glutamine catabolism — metabolic shifts that directly determine polarization state. Second, they orchestrate epigenetic regulation through DNA methylation changes, histone deacetylation and acylation, and non-coding RNA pathways, enabling durable reprogramming of macrophage identity. Third, sirtuins mediate interactions between macrophages and other immune cells, including T cells and neutrophils, shaping the broader cardiac immune environment.

The review also catalogs natural phytomedicine compounds — resveratrol, pterostilbene, astragaloside IV, quercetin, dihydromyricetin, berberine, honokiol, and ginsenosides Rc, Rg1, and Rg3 — that activate or modulate sirtuins to favorably shift macrophage polarization in preclinical HF models.

As a narrative review based solely on existing literature, direct causal claims require validation in clinical trials. Nevertheless, this work provides a structured translational framework for developing sirtuin-targeted, immune-modulating therapies for heart failure, including novel natural product candidates.